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Massive Transfusion Protocols in Non-Trauma Patients:

A Systematic Review and Meta-Analysis

Nora Sommer, BM; Beat Schnüriger, MD; Daniel Candinas, MD; Tobias Haltmeier, MD

Department of Visceral Surgery and Medicine, Division of Acute Care Surgery, Inselspital, Bern

University Hospital, Bern, Switzerland

Author’s email addresses:

Nora Sommer: [email protected]

Beat Schnüriger: [email protected]

Daniel Candinas: [email protected]

Tobias Haltmeier: [email protected]

Address of correspondence: Tobias Haltmeier, MD, FACS, Department of Visceral Surgery and

Medicine, Division of Acute Care Surgery, Inselspital, Bern University Hospital, University of

Bern, Bern, Switzerland, Phone: +41 31 632 59 00, Fax: +41 31 632 59 99. E-mail:

[email protected]

Disclosure: Nora Sommer, Beat Schnüriger, Daniel Candinas, and Tobias Haltmeier have no

conflicts of interest or financial ties to disclose.

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Journal of Trauma and Acute Care Surgery, Publish Ahead of Print DOI: 10.1097/TA.0000000000002101

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

source: https://doi.org/10.7892/boris.125763 | downloaded: 13.8.2020

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Abstract

Background

Massive bleeding is a major cause of death both in trauma and non-trauma patients. In trauma

patients, the implementation of massive transfusion protocols (MTP) led to improved outcomes.

However, the majority of patients with massive bleeding are non-trauma patients.

Objectives

To assess if the implementation MTP in non-trauma patients with massive bleeding leads to

improved survival.

Data sources

National Library of Medicine’s Medline database (PubMed).

Study eligibility criteria

Original research articles in English language investigating MTP in non-trauma patients.

Participants

Non-trauma patients with massive bleeding 18 years of age.

Intervention

Transfusion according to MTP versus off-protocol.

Study appraisal and synthesis methods

Systematic literature review using PubMed. Outcomes assessed were mortality and transfused

blood products. Studies that compared mortality of MTP and non-MTP groups were included in

meta-analysis using Mantel-Haenszel random effect models.

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Results

A total of 252 abstracts were screened. Of these, 12 studies published 2007-2017 were found to

be relevant to the topic, including 2,475 patients. All studies were retrospective and comprised

different patient populations. Most frequent indications for massive transfusion were

perioperative, obstetrical and gastrointestinal bleeding, as well as vascular emergencies. Four out

of the five studies that compared the number of transfused blood products in MTP and non-MTP

groups revealed no significant difference. Meta-analysis revealed no sigificant effect of MTP on

the 24-hour mortality (OR 0.42, 95%CI 0.01-16.62, p=0.65) and a trend towards lower one-

month mortality (OR 0.56, 95%CI 0.30-1.07, p=0.08).

Limitations

Heterogeneous patient populations and MTP in the studies included.

Conclusions and implications of key findings

There is limited evidence that the implementation of MTP may be associated with decreased

mortality in non-trauma patients. However, patient characteristics, as well as the indication and

definition of MTP were highly hetergenous in the available studies. Further prospective

investigation into this topic is warranted.

Study type

Systematic review and meta-analysis

Level of evidence

Level III

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Key words

Hemorrhage, non-trauma emergency, blood component transfusion, transfusion protocol, meta-

analysis.

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Background

In patients receiving massive transfusion a high mortality rate has been described, both in the

trauma and non-trauma setting.(1-3) Rose et al. report an in-hospital mortality rate of 34% in a

mixed patient population receiving massiv transfusion.(2) Halmin et al., in a nationwide cohort

study assessing the epidemiology of massive transfusion in Sweden and Denmark, report a 30-

day mortality of 24.8%.(1) Turan et al. investigated the mortality after massive transfusion in

patients undergoing non-cardiac surgery using the American College of Surgeons National

Surgical Quality Improvement Program (NSQIP) database. In this study, a postoperative 30-day

mortality of 17% was found in patients undergoing massive transfusion.(3) Common causes for

massive hemorrhage in non-trauma patients are gastrointestinal bleeding, ruptured abdominal

aortic aneurisms, as well as surgical or obstetrical bleeding.(4-7) In the above-mentioned cohort

study conducted in Sweden and Denmark, massive transfusion was reported with an incidence of

2.5 (Sweden) and 4.5 (Denmark) per 10,000 person years.(1) Turan et al. report massive

transfusion in 7,485 out of 917,651 patients in NSQIP 2006-2009, corresponding to 0.8%.(3)

Most recent studies investigating the pathophysiology and treatment of hemorrhage focused on

trauma patients.(4, 6-11) However, major surgery for non-traumatic disease has been reported to

be the most common cause of massive bleeding, followed by trauma and obstetric bleeding.

Although the overall incidence of massive bleeding is relatively small, it remains an important

source of mortality in non-trauma patients.(1, 3)

The goal of massive transfusion protocols (MTP) is to rapidly provide blood products to

hemodynamically unstable bleeding patients and to treat coagulopathy. This includes the

availability of blood products in predefined ratios and the rapid transport and transfusion of these

products.(12) MTP have been successfully implemented in trauma patients and have been shown

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to improve outcomes in this patient population(12), including lower mortality(13), a lower risk

of multi-organ failure, higher rate of fascial closure(14), and decreased use of blood

products(15). The current guidelines of the American College of Surgeons Trauma Quality

Improvement Program (ACS TQIP), support the implementation of MTP in the early care of

trauma patients.(16)

In sumary, massive transfusion is rare but associated with a high mortality rate in non-trauma

patients. Taking into account the above-mentioned improved outcomes related to MTP in trauma

patients, non-trauma patients may benefit from MTP, too. The aim of this systematic review and

meta-analysis was, therefore, to assess the use MTP and its effect on outomes in non-trauma

patients. We hypothesized that the implementation MTP in non-trauma patients with massive

bleeding leads to improved survival.

Methods

This is a systematic literature review and meta-analysis investigating the role of MTP in bleeding

non-trauma patients. PRISMA guidelines(17, 18) were followed thoughout the literature search,

meta-analysis, reporting of the data, and discussion. (Table 5)

Literature search

A systematic literature search was conducted using the National Library of Medicine's Medline

database (PubMed)(19). The search strategy was based on the PICOS process.(20, 21) When

possible, Medical Subject Headings (MeSH)(22) were used as search terms. The following

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search terms were used for the PubMed search:

massive AND transfusion AND protocol AND (surgical OR medical)

massive AND transfusion AND protocol AND (surgical OR medical); Filters: review

(((blood transfusion) AND exchange transfusion, whole blood) AND surgical procedures,

operative) AND patient care

(((blood transfusion[MeSH Terms]) AND exchange transfusion, whole blood[MeSH

Terms]) AND surgical procedures, operative[MeSH Terms]) AND patient care[MeSH

Terms]

massive transfusion protocol AND (surgical procedures, operative OR patient care)

Only original research articles in english language were included. Exclusion criteria were articles

including patients under 18 years of age and non-original research articles such as literature

reviews and letters to the editor.

All abstracts of the articles found were screened. If the abstracts were relevant to the topic, the

corresponding articles were included in the review. Articles relevant to the topic that were cited

in articles found on PubMed using the above-named search terms were also included in the

review, as well as articles that described MTP both trauma and non-trauma patients.

Quality assessment

The quality of the studies included in this systematic literature review and meta-analysis was

assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies (23) with mortality as

outcome measure.

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Outcomes

The primary outcome assessed was the 24-hour and one-month mortality. Secondary outcomes

were the number of blood products transfused, including packed red blood cells (PRBC), fresh

frozen plasma (FFP), and platetelts, as well as transfusion ratios.

Statistical analysis

Studies that compared the mortality rate of MTP and non-MTP groups in non-trauma patients

specifically were included in the meta-analysis. The number of survivors and non-survivors in

MTP and non-MTP groups reported in these studies was extracted for the meta-analysis.

Meta-analysis for the 24-hour and one-month mortality was performed using a Mantel-Haenszel

random effect model. The estimated effect size for the 24-hour and one-month mortality was

reported as odds ratio (OR) and 95% confidence interval (CI) for each study that compared MTP

and non-MTP groups, as well as for the overall cohort. Heterogeneity of included studies was

assessed using cochran's Q statistic and I2.(24, 25) No funnel plots were created due to the small

number of studies included in meta-analysis.

Statistical analysis was performed using Review Manager (RevMan) Version 5.3. (Copenhagen:

The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Results

Articles included

The literature search and included articles are outlined in Figure 1. A total of 252 abstracts were

screened. Twelve articles were found to be relevant to the topic.(4-11, 26-29) All articles were

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published between 2007 and 2017. Included studies enrolled a total of 2,475 patients. Of these,

1,620 were non-trauma patients. (Table 1)

Seven studies included both trauma and non-trauma patients.(4-7, 9, 10, 29) The non-trauma

groups in these studies were comprised of patients undergoing emergency or elective surgery(4-

10, 29), as well as patients with gastrointestinal bleeding(4-7, 9, 29), obstetric hemorrhage(4, 5,

7, 10, 29), and vascular emergencies(4, 6, 7, 9, 29). In three of these seven studies, analysis was

performed using a mixed trauma/non-trauma population, comprising 91%(10), 76%(29), and

38.2-100% (range, six hospitals included)(5) non-trauma patients. In four studies, trauma and

non-trauma patients were analyzed separaterly.(4, 6, 7, 9) (Table 1)

Five studies investigated non-trauma patients only.(8, 11, 27) (26, 28) Three studies focused on

patients with bleeding due to obstetric complications only(11, 26, 27), whereas Johansson et al.

analyzed patients with massive bleeding after ruptured abdominal aortic aneurysm

exclusively.(28) Martinez-Calle et al. included non-trauma patiens undergoing oncolocic

surgery, cardiovascular surgery, other surgery, and non-surgical treatment for massive

bleeding.(8)

Quality assessment

Table 4 shows the quality assessment of the studies included based on the NOS. None of the

studies included used a matched study desing or adjusted for counfounders. Therefore, based on

the criteria of the NOS, no study received stars for the comparability of the study groups. The

studies by Chay(5), Gutierrez(27), and Goodnough(26) did not receive stars for the outcome

categories, as mortality was not reported as an outcome measure in these studies. Furthermore,

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the studies by Gutierrez and Goodnough did not include a controll group and consequently did

not recieve a star in this category. In the studies by Chay(5) and Johanson(28) the number of

survivors and death was not reported. These studies therefore did not receive stars for the

adequacy of follow-up category.

Patient characteristics

The majority of the patients included were male, ranging from 64.4 to 87.1%.(4, 6-10, 28)

Exceptions were the studies assessing obstetric patients only.(11, 26, 27) The age of included

patients ranged from 29.9 to 73.0 years. (Table 1)

Three studies reported comorbidities of the patients included.(4, 10, 28) Balvers et al. showed

that 26% of patients before the introduction of a MTP and 25% of the patients after the

introduction had no known comorbidities. The remaining patients suffered from cardiovascular

(57% in both groups) or pulmonary disease (8% and 7%), bleeding diathesis (4% and 3%), and

other comorbidities (5% and 8%).(10) Johansson et al. found comorbidities in 74% and 73% of

patients before and after the implementation of a MTP, respectively.(28) In the study by

Baumann Kreuziger et al. the mean overall APACHE II score was 27, while it was significantly

lower in trauma than in non-trauma patients (25 vs. 29, p<0.05).(4) The other studies did not

report comorbidities of included patients.(5-9, 11, 26, 27, 29)

Definition of massive transfusion

The definition of massive transfusion was given in 9 articles. (4-11, 29) Massive transfusion was

most commonly defined as the transfusion of 10 or more units of PRBC in the first 24 hours after

hospital admission.(4-7, 9, 29) Other definitions were the transfusion of 5 or more units of PRBC

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in the first twelve hours after hospital admission(10), the replacement of the whole blood volume

(7% of ideal body weight in adults) in a 24 hour period (8), the replacement of 50% of the whole

blood volume in a three hour period(8), the loss of ≥ 1500 ml blood in ten minutes(8), or the

transfusion of 4 or more units of PRBC.(11)

Indications for massive transfusion

Indications for massive transfusion in non-trauma patients were bleeding during or after surgery

(frequency reported as 11.2 to 82.2%)(4-10, 29), obstetrical bleeding (4.4 to 100%)(4, 5, 7, 10,

11, 26, 27, 29), gastrointestinal bleeding (20.0 to 66.7%)(4-7, 9, 29), vascular emergencies (2.7

to 100%)(4, 6, 7, 9, 28, 29), or other reasons (13.0 to 17.8%).(4, 8, 10)

Blood product transfusion

Transfused blood products are shown in Table 2. Of the five studies that compared the number of

transfused units of blood products in non-trauma patients before and after the implementation of

a MTP(6, 8, 10, 11, 28), four studies revealed no statistically significant difference of the number

of transfused units of PRBC, FFP, and PLT.(6, 8, 10, 11) In the study investigating the

implemantation of a transfusion protocol in patients with ruptured abdominal aortic aneurysms, a

significantly higher number of FFP and PLT during surgery, but lower postoperative transfusion

of PRBC, FFP and PLT were found after implementation of the protocol.(28)

Transfusion ratios (FFP:PRBC, PLT:PRBC) were reported in 9 studies.(4-11, 29) Of these, five

studies compared transfusion ratios in MTP and non-MTP groups.(6, 8, 10, 11, 29) Sinha et al.

reported significantly higher FFP:PRBC and PLT:PRBC transfusion ratios in the MTP group

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compared to the Pre-MTP group.(29) In the study by Balvers et al. a significantly higher

proportion of patients in the MTP-group received PRBC:FFP transfusion ratios ≤ 1.1 compared

to the Pre-MTP group.(10) In the other 3 studies, no statistically significant difference of the

transfusion ratios in the MTP and non-MTP groups was found.(6, 8, 11) (Table 2)

Overactivation of MTP, defined as the proportion of patients with MTP activation that received

≤ 10 units of PRBC, was reported in four studies. The rate of MTP overactivation found in these

studies was high, ranging from 53.8% to 65%.(4, 6, 7, 9) (Table 2)

McDaniel et al. analyzed the wasted units of blood products before and after the implementation

of a MTP. A significantly increased waste of platelets was observed in patients with MTP

activation compared to patients without MTP activation (12.8% vs. 8.1%, p=0.046).(6)

Impact of MTP on mortality

Four studies compared the one-month mortality in patients with and without MTP activation(6,

8, 10, 28) Of these four studies, two studies found a significantly lower 30-day mortality in the

MTP group compared to the non-MTP group (Martinez-Calle et al.: 18.1% and 13.0% vs. 30.2%.

[two MTP groups], p=0.010(8); Johansson et al.: 34% vs. 56%, p=0.02(28)). In contrast,

McDaniel et al. found no significant difference of the 30-day mortality in the MTP group and

non-MTP group (50.0% vs. 42.1%, p=0.207).(6) Likewise, the study by Balvers et al. revealed

no significant difference of the 28-day mortality after the implementation of a MTP (35% vs.

34%, p=0.801).(10) (Table 3)

Three studies compared the 24-hour mortality in MTP and non-MTP groups. In two of these

three studies, the 24-hour mortality was not significantly different between the MTP and non-

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MTP group (McDaniel et al.: 30.8% vs. 15.8%, p=0.155(6); Balvers et al.: 15% vs. 12%,

p=0.386(10)). On the other hand, Martinez-Calle et al. found a significantly lower 24-hour

mortality in the MTP group compared to the non-MTP group (0.0% and 1.1% vs. 7.3% [two

MTP groups], p=0.002).(8) (Table 3)

Meta-analysis included four studies that reported mortality of MTP and non-MTP groups in non-

trauma patients specifically.(6, 8, 11, 28) Meta-analysis revealed no statistically sigificant effect

of MTP on the 24-hour mortality rate (OR 0.42, 95%CI 0.01-16.62, p=0.65) and one-month

mortality (OR 0.56, 95%CI 0.30-1.07, p=0.08). (Figure 2)

Discussion

The aim of this systematic literature review and meta-analysis was to find scientific evidence for

the use of MTP in bleeding non-trauma patients. Twelve studies including patients with

perioperative, gastrointestinal, and obstetrical bleeding, as well as bleeding from vascular

emergencies, were assessed. (Figure 1)

Two studies found a significantly lower mortality associated with the introduction of a MTP in

bleeding non-trauma patients.(8, 28) In two other studies that analyzed mortality before and after

implementation of a MTP, no statistically significant effect of the introduction of a MTP on

mortality was found.(6, 10) Furthermore, one study that found a lower mortality in the MTP

group included patients with ruptured aortic aneurysm only, which is a distinct group of patients

with a very high mortality and morbidity.(30, 31) On the other hand, meta-analysis including the

same studies showed a trend towards a lower one-month mortality rate. Based on these results it

is possible that MTP may lower the mortality rate in bleeding non-trauma patients. Taking into

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account the small number of studies eligible for inclusion in meta-analysis, more statistical

power is needed to confirm this hypothesis.

Another reason for the non-significant effect of MTP on mortality found in the current meta-

analysis may be delayed MTP activation in the studies included. In major trauma patients, severe

bleeding is anticipated and MTP are readily activated according to clearly defined criteria.(16) In

non-trauma patients, the onset of bleeding may be more subtle, delaying the activation of MTP.

Furthermore, well-defined criterial for massive transfusion in non-trauma patients are lacking.

Martinez et al. report proactive triggering of MTP in only 20% in non-trauma patients. In the

other 80%, MTP was automatically activated by the blood bank after the transfusion of more

than 8 PRBC.(8) In the study by McDaniel et al. MTP activation accelerated the delivery of of

FFP and platelets. However, MTP activation was not associated with improved survival in this

study.(6)

Although one of the goals of MTP is to achieve higher plasma and platelets to PRBC transfusion

ratios, FFP:PRBC and/or PLT:PRBC transfusion ratios did not meet the currently recommended

ratios of 1:1:1 or 1:1:2(32) in four studies.(8, 9, 11, 29) (Table 2) This finding is surprising, as

with the introduction of a MTP, predefined ratios of blood products should be available for

transfusion.(12, 15, 33-35) A possible explantation for the lower than recommended transfusion

ratios in these studies may be a delayed MTP activation with unbalanced PRBC transfusion prior

to the activation of the protocol.(8)

A high rate of MTP overactivation was found in four studies.(4, 6, 7, 9) The identification of

non-trauma patients that require MTP activation may be challenging as specific criteria are still

lacking. In trauma patients, on the contrary, there are well established criteria for massive

transfusion and MTP activation, such as the ACS TQIP Best Practice Guidelines(16), the

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Assessment of Blood Consumption (ABC) score(36-38), the Trauma Associated Severe

Hemorrhage (TASH) score(39), the algorithm developped for combat casualty patients by

McLaughlin and collegues(40), the Revised Assessment of Bleeding and Transfusion (RABT)

score(41), and the Massive Transfusion Score (MTS)(42). The absence of defined criteria for

massive transfusion in non-trauma patients most likely explains the high overactivation rate in

this patient population.

The study of McDaniel et al. was the only one that analyzed the waste of blood products. An

increased waste of platelets was found after the introduction of a MTP.(6) The waste of blood

products associated with MTP could potentially be prevented, as unused blood products may be

provided to other patients if they are returned promptly to the blood bank.(6) Furthermore, timely

termination of the MTP once the endpoints of transfusion are achieved may reduce the waste of

blood products. The ACS TQIP lists several criteria for the termination of MTP, including

downgrading to goal-directed transfusion if bleeding has been controlled by surgery or

angioembolization, further resuscitation is futile, and - in patients with no active bleeding -

laboratory findings indicate adequate blood coagulation.(16) Although the ACS TQIP criteria for

the termination of MTP were elaborated for trauma patients, they may also be useful in non-

trauma patients. Further studies will need to evaluate the criteria for MTP termination in non-

trauma patients specifically.

Non-trauma patients included in the current review had many comorbidities, especially from

cardiovascular origin.(4, 10, 28, 29) (Table 1) Trauma patients are typically younger and have

less comorbidities than the non-trauma patients included in the current review. Furthermore,

polytrauma patients may bleed from multiple injuries, whereas bleeding is often localized in non-

trauma patients, e.g. in patients with gastrointestinal bleeding or bleeding during cardio-vascular

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surgery. Both trauma and non-trauma patients may suffer from profuse bleeding due to

coagulopathy. However, due to the above-mentioned cardiovascular comorbidities, drug-induced

coagulopathy is more likely in non-trauma than in trauma patients.(43) When extrapolating

indications and goals of MTP from trauma to non-trauma patients, the different characteristics of

these two patient populations need to be considered.

This systematic literature review and meta-analysis has several limitations. First, all studies were

retrospective. Second, three studies analyzed mixed cohorts of non-trauma and trauma patients(5,

10, 29), while others focused on a specific group of patients(11, 26-28). Third, the total number

of patients that were included in meta-analysis was relatively small, limiting the validity of the

results. Fourth, the quality of the studies included varied and was poor in some studies. (Table 4)

Fifth, massive transfusion protocols, including the indication for MTP activation and predefined

transfusion ratios, differed between the studies included. In order to take into account the

heterogeneity of the studies included, only studies reporting outcomes of MTP- and non-MTP

groups in non-trauma patients specifically were included in the quantitative analysis.

Furthermore, a radom-effects model was chosen for meta-analysis.

Conclusion

Based on the current literature review and meta-analysis, there is limited evidence that the

implementation of MTP may be associated with decreased mortality in non-trauma patients.

Both, overactivation and an increased waste of blood products have been reported with the

introduction of MTP. However, patient characteristics, as well as the indication and definition of

MTP were highly hetergenous in the available studies. Further prospective investigation into this

topic is warranted.

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Author contribution statement

Literature search: NS and TH. Study design: TH and BS. Data collection: NS and TH. Data

analysis: TH and BS. Data interpretation: TH, NS, BS, and DC. Writing: NS, TH, and BS.

Critical revision: TH, BS, and DC.

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25. Hak T, Rhee Hv, Suurmond R. How to interpret results of meta-analysis (Version 1.3).

Accessed 08-20-2018. Available from: https://repub.eur.nl/pub/80102.

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treat: transfusion medicine support of obstetric services. Transfusion. 2011;51(12):2540-8.

27. Gutierrez MC, Goodnough LT, Druzin M, Butwick AJ. Postpartum hemorrhage treated

with a massive transfusion protocol at a tertiary obstetric center: a retrospective study. Int J

Obstet Anesth. 2012;21(3):230-5.

28. Johansson PI, Stensballe J, Rosenberg I, Hilslov TL, Jorgensen L, Secher NH. Proactive

administration of platelets and plasma for patients with a ruptured abdominal aortic aneurysm:

evaluating a change in transfusion practice. Transfusion. 2007;47(4):593-8.

29. Sinha R, Roxby D, Bersten A. Experience with a massive transfusion protocol in the

management of massive haemorrhage. Transfus Med. 2013;23(2):108-13.

30. Bown MJ, Sutton AJ, Bell PR, Sayers RD. A meta-analysis of 50 years of ruptured

abdominal aortic aneurysm repair. Br J Surg. 2002;89(6):714-30.

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32. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ,

Brasel KJ, Bulger EM, Callcut RA, et al. Transfusion of plasma, platelets, and red blood cells in

a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized

clinical trial. JAMA. 2015;313(5):471-82.

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33. Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris JA, Jr., St Jacques P,

Young PP. Damage control hematology: the impact of a trauma exsanguination protocol on

survival and blood product utilization. J Trauma. 2008;64(5):1177-82; discussion 82-3.

34. Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, Cocanour CS,

Balldin BC, McKinley BA. Fresh frozen plasma should be given earlier to patients requiring

massive transfusion. J Trauma. 2007;62(1):112-9.

35. Repine TB, Perkins JG, Kauvar DS, Blackborne L. The use of fresh whole blood in

massive transfusion. J Trauma. 2006;60(6 Suppl):S59-69.

36. Nunez TC, Voskresensky IV, Dossett LA, Shinall R, Dutton WD, Cotton BA. Early

prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption)?

J Trauma. 2009;66(2):346-52.

37. Cotton BA, Dossett LA, Haut ER, Shafi S, Nunez TC, Au BK, Zaydfudim V, Johnston

M, Arbogast P, Young PP. Multicenter validation of a simplified score to predict massive

transfusion in trauma. J Trauma. 2010;69 Suppl 1:S33-9.

38. Cantle PM, Cotton BA. Prediction of Massive Transfusion in Trauma. Crit Care Clin.

2017;33(1):71-84.

39. Yucel N, Lefering R, Maegele M, Vorweg M, Tjardes T, Ruchholtz S, Neugebauer EA,

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trauma. J Trauma. 2006;60(6):1228-36; discussion 36-7.

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predictive model for massive transfusion in combat casualty patients. J Trauma. 2008;64(2

Suppl):S57-63; discussion S.

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41. Joseph B, Khan M, Truitt M, Jehan F, Kulvatunyou N, Azim A, Jain A, Zeeshan M, Tang

A, O'Keeffe T. Massive Transfusion: The Revised Assessment of Bleeding and Transfusion

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43. Kreuziger LMB, Salzman J, Subramanian AT, Morton CT, Dries DJ. Massive

Transfusion in Non-Trauma Patients. Blood. 2011;118(21):3376.

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Figures and Tables Legend

Figure 1. *Records relevant to the topic that were cited in articles identified by the literature

search

Figure 2. MTP: massive transfusion protocol, CI: confidence interval, M-H: Mantel–Haenszel

statistics.

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25

ACCEPTED


26

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27

Table 1. Studies included

Author, Journal, Year Study type Study

size*

Patient characteristics* Age Indication for MTP

activation

MTP/Non-

MTP*

(n=) (Years)

Dutta et al., Am J

Perinatol, 2017

Retrospective

single center

62 Obstetric: 62 (100) Pre-MTP: 29.9±1.0‡

Post-MTP: 32.7±1.2‡

Clinical judgement 6/56

Chay et al., Vox Sang,

2016

Retrospective

multicenter

434 Major surgery: 130 (30), gastrointestinal bleeding: 109 (25), obstetric: 26 (6),

trauma: 169 (39)

- Clinical judgement 434/0

Martinez-Calle et al.,

Med Intensiva, 2016

Retrospective

single center

304 Oncologic surgery: 88 (28.9), cardiovascular surgery: 105 (34.5), other surgery: 57

(18.8), non-surgical bleeding: 54 (17.8)

Pre-MTP: 62 (52-74)+

MTP: 62 (50-71)+

Replacement of whole blood

volume in 24h/Replacement

of 50% of blood volume in

3h/Blood loss > 1500ml in

10min/Triggered by blood

bank if > 8 PRBC used

208/96

Wijaya et al.,

Singapore Med J, 2016

Retrospective

single center

46 GIT bleeding: 12 (26.1), ruptured AAA: 3 (6.5), ruptured splenic artery aneurysm: 1

(2.2), intraoperative bleeding: 1 (2.2), postoperative bleeding: 1 (2.2), trauma: 28

(60.9)

55.67±19.36‡ Clinical judgement 46/0

Balvers et al., J Emerg

Trauma Shock, 2015

Retrospective

single center

547 Trauma: 48 (8.8), surgery: 348 (63.1), obstetric: 22 (4.0), internal Medicine: 69

(12.6), other: 60 (11.0)

Pre-MTP: 65 (51-76)+

MTP: 65 (52-73)+

SBP <90mmHg with no

response to fluid

administration and suspicion

of massive bleeding

115/432

Baumann Kreuziger et

al., Transfus Med,

2014

Retrospective

single center

133a Vascular rupture: 23 (18.4), GIT bleeding: 16 (12.8), cardiothoracic surgery: 11 (8.8),

obstetric: 5 (4.0), thrombosis: 2 (1.6), orthopedic: 1 (0.8), trauma: 62 (49.6), other:

5 (4.0)

53±18.6‡ Clinical judgement 125/8

McDaniel et al., J Am

Coll Surg, 2013

Retrospective

single center

164 GIT bleeding: 21 (12.8), medical bleeding for other reasons: 6 (3.7),

postsurgical/procedural complications: 18 (11.0), vascular emergencies: 18 (11.0),

cerebral hemorrhage: 1 (0.6), trauma: 100 (61.0)

MTP: 57.9±19.8‡

nMTP: 64.6±16.4‡

Clinical judgement 52/112

Sinha et al., Transfus

Med, 2013

Retrospective

single center

152 Ruptured AAA: 31 (20), cardiac surgery: 12 (8), other surgery: 29 (19), GIT bleeding:

23 (15), obstetric: 16 (11), liver transplantation: 4 (3), trauma: 37 (24)

61 (40-78)+ Clinical judgement 83/69 ACCEPTED


28

Morse et al., Am Surg,

2012

Retrospective

single center

439 GIT bleeding: 18 (4.1), intraopoerative bleeding: 13 (3.0), obstetric: 5 (1.1),

ruptured AAA: 1 (0.2), trauma: 402 (91.6)

37.5±0.74# Clinical judgement 439/0

Gutierrez et al., Int J of

Obstet Anesth, 2012

Retrospective

single center

31 Obstetric: 31 (100) 33.5±6.1‡ Clinical judgement 31/0

Goodnough et al.,

Transfusion, 2011

Retrospective

single center

31 Obstetric: 31 (100) - Emergent need for blood

products (not further

specified)

31/0

Johansson et al.,

Transfusion, 2007

Retrospective

single center

132 Ruptured AAA: 132 (100) Pre-MTP: 73 (51-84)+

MTP: 71 (48-89)+

Massive bleeding (not

further specified)

50/82

*Values are numbers (percentages). +Median (IQR). #Mean±SEM. ‡Mean±SD. aIncluding 8 patients that were transfused off-protocol and were not included in the analysis.

MTP: massive transfusion protocol, PRBC: packed red blood cells, GIT: gastrointestinal tract, AAA: abdominal aortic aneurism, SBP: systolic blood pressure.

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29

Table 2. Blood products, transfusion ratios, and overactivation

Author, Year,

Journal

Units transfused per patient Transfusion ratios Over-

activation

PRBC FFP Platelets

Dutta, E. H., et al.,

2017, Am J Perinatol

Pre-MTP: 6 (5-8)+

MTP: 7 (5-9)+

p=0.85

Pre-MTP: 4 (1-5)+

MTP: 2 (0-4)+

p=0.28

Pre-MTP: 0 (0.0-0.6)+

MTP: 0 (0.0-0.6)+

p=0.63

FFP:PRBC

Pre-MTP: 0.5 (0.1-0.6)+, MTP: 0.3 (0.0-

0.5)+, p=0.31

PLT:PRBC

Pre-MTP: 0.0 (0.0-0.6)+, MTP: 0.0 (0.0-

0.7)+, p=0.42

-

Chay et al., 2016,

Vox Sang Range 5-12† Range 4-8† Range 3- 8†

FFP:PRBC

Range 0.6-0.8†

PLT:PRBC

Range 0.6-0.8†

-

Martinez-Calle et

al., 2016, Med

Intensiva

(two MTP groups)

Pre-MTP: 9 (6)+

MTP: 19 (9)+

p=0.688

Pre-MTP: 5 (6)+

MTP: 77 (37)+

p=0.238

Pre-MTP: 1 (2)+

MTP: 5 (2)+

p=0.751

FFP:PRBC

Pre-MTP: 0.44 (0.30-0.67)+, MTP: 0.57

(0.33-0.77)+ and 0.55 (0.33-0.79)+,

p=0.053

PLT:PRBC

Pre-MTP: 0.10 (0.0- 0.15)+, MTP: 0.11

(0.0-0.18)+ and 0.1 (0.0-0.17)+, p=0.429

-

Wijaya et al., 2016,

Singapore Med J - - -

FFP:PRBC: 0.655±0.192‡

PLT:PRBC: 0.141±0.072‡ 11 (61.1)

Balvers et al., 2015,

J Emerg Trauma

Shock

Pre-MTP: 8 (6-12)+

MTP: 8 (7-13)+

p=0.279

Pre-MTP: 6 (3-9)+

MTP: 6 (4-11)+

p=0.224

Pre-MTP: 2 (1-3)+

MTP: 2 (0-4)+

p=0.139

PRBC:FFP ≤ 1.1

Pre-MTP: 70 (37)*, MTP: 168 (47)*,

p=0.014

PRBC:PLT ≤ 1.1

Pre-MTP: 119 (62)*, MTP: 230 (65)*,

p=0.514

-

Baumann Kreuziger

et al., 2014,

Transfus Med

8.7±7.0‡ 6.2±5.7‡ 1.5±1.3‡

Plasma:PRBC

<1:4: 7 (11.1)*

1:4-1:2: 11 (17.5)*

1:2-1:1: 37 (58.7)*

>1:1: 8 (12.7)*

41 (65)

McDaniel et al.,

2013, J Am Coll Surg

Non-MTP: 12.2±9.0‡

MTP: 12.6±11.5‡

p=0.864

Non-MTP: 8.9±8.7‡

MTP: 9.2±8.0‡

p=0.631

Non-MTP: 6.5±8.6‡

MTP: 7.2±6.7‡

p=0.183

FFP:PRBC

MTP: 0.79:1±0.34:1‡, Non-MTP:

0.65:1±0.39:1, p=0.282

PLT:PRBC

MTP: 0.61:1±0.42:1‡, Non-MTP:

0.53:1±0.54:1, p=0.476

14 (53.8)

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30

Sinha et al., 2013,

Transfus Med

Pre-MTP: 16 (12-20)+

MTP: 14 (11-21)+

Pre-MTP: 6 (5-10)+

MTP: 10 (7-17)+

Pre-MTP: 2 (1-3)+

MTP: 3 (2-4)+

FFP:PRBC

Pre-MTP: 1:2.4 (1:1.8-1:3.4)+, MTP:

1:1.4 (1:1.2-1:2.0)+, p<0.001

PLT:PRBC

Pre-MTP: 1:10 (1:6.0-1:14.0)+, MTP: 1:6

(1:4.1-1:8.0)+, p<0.001

-

Morse et al., 2012,

Am Surg 12.5±2.0# 7.9±1.3# 8.6±1.4#

PRBC:FFP: 1:2.2±0.3#

PRBC:PLT: 1:2.3±0.4# 20 (54)

Gutierrez et al.,

2012, Int J of Obstet

Anesth

3.0 (1.8-7.0)+ 3.0 (1.5-5.5)+ 1.0 (0.0-2.5)+ - -

Goodnough et al.,

2011, Transfusion 5.0 (4.0-7.5)+ 2.0 (0.0-4.0)+ 1.0 (0.0-1.0)+ - -

Johansson et al.,

2007, Transfusion

OR: no difference

ICU: Pre-MTP: 6 (0-54)+,

MTP: 2 (0-30)+, p<0.05

OR: Pre-MTP: 0 (0-3)+,

MTP: 4 (2-16)+, p<0.05

ICU: Pre-MTP: 1 (0-6)+,

MTP: 0 (0-4)+, p<0.05

OR: Pre-MTP: 7 (0-46)+,

MTP: 11 (2-42)+, p<0.05

ICU: Pre-MTP: 4 (0-32)+,

MTP: 2 (0-12)+, p<0.05

- -

*Numbers (percentage). +Median (IQR). †Median. ‡Mean ± SD. #Mean ± SEM.

MTP: massive transfusion protocol. PRBC: packed red blood cells. FFP: fresh frozen plasma. PLT: platelets. AAA: abdominal aortic aneurysm. OR: operating room.

ICU: intensive care unit.

Overactivation: < 10 units of PRBC transfused for patients with activated MTP.

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Table 3. 24-hour and one-month mortality

Author, Year, Journal 24-hour mortality One-month mortality*

n (%) n (%)

Dutta, E. H., et al., 2017, Am J Perinatol Pre-MTP: 0 (0)

MTP: 0 (0)

Pre-MTP: 0 (0)

MTP: 0 (0)

Chay et al., 2016, Vox Sang - -

Martinez-Calle et al., 2016, Med Intensiva

Pre-MTP: 7 (7.3)

MTP: 0 (0.0) and 1 (1.1) (2 MTP groups)

p=0.002

Pre-MTP: 29 (30.2)

MTP: 21 (18.1) and 12 (13.0) (2 MTP groups)

p=0.010

Wijaya et al., 2016, Singapore Med J - -

Balvers et al., 2015, J Emerg Trauma Shock

Pre-MTP: 23 (12.0)

MTP: 52 (15.0)

p=0.386

Pre-MTP: 65 (34)

MTP: 124 (35)

p=0.801

Baumann Kreuziger et al., 2014, Transfus Med - -

McDaniel et al., 2013, J Am Coll Surg

Non-MTP: 6 (15.8)

MTP: 8 (30.8)

p=0.155

Non-MTP: 16 (42.1)

MTP: 13 (50.0)

p=0.207

Sinha et al., 2013, Transfus Med - -

Morse et al., 2012, Am Surg MTP: 15 (41.0) MTP: 18 (49.0)

Gutierrez et al., 2012, Int J of Obstet Anesth - -

Goodnough et al., 2011, Transfusion - -

Johansson et al., 2007, Transfusion -

Pre-MTP: 46 (56)

MTP: 17 (34)

p=0.02

(death in OR excluded)

*Fisher’s exact test, studies that reported mortality in non-trauma patients specifically.

MTP: massive transfusion protocol, OR: operating room, CI: confidence interval. ACCEPTED


32

Table 4. Quality assessment using the Newcastle-Ottawa Scale for cohort studies

Author, Journal, Year Selection Comparability Outcome Total

Representative-

ness of the

exposed cohort

Selection of the

non-exposed

cohort

Ascertainment of

exposure

Demonstration

that outcome of

interest was not

present at start of

study

Assessment of

outcome

Follow-up long

enough for

outcomes to occur

Adequacy of

follow up of

cohorts

Dutta et al., Am J

Perinatol, 2017 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Chay et al., Vox Sang,

2016 ✻ ✻ ✻ ✻ 4

Martinez-Calle et al.,

Med Intensiva, 2016 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Wijaya et al., Singapore

Med J, 2016 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Balvers et al., J Emerg

Trauma Shock, 2015 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Baumann Kreuziger et

al., Transfus Med, 2014 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

McDaniel et al., J Am

Coll Surg, 2013 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Sinha et al., Transfus

Med, 2013 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Morse et al., Am Surg,

2012 ✻ ✻ ✻ ✻ ✻ ✻ ✻ 7

Gutierrez et al., Int J of

Obstet Anesth, 2012 ✻ ✻ ✻ 3

Goodnough et al., ✻ ✻ ✻ 3 ACCEPTED


33

Transfusion, 2011

Johansson et al.,

Transfusion, 2007 ✻ ✻ ✻ ✻ ✻ ✻ 6

Quality assessment with mortality as outcome.

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34

Table 5. PRISMA 2009 Checklist

Section/topic # Checklist item Reported on

page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured

summary

2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility

criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions

and implications of key findings; systematic review registration number.

Abstract

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 1, 2

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions,

comparisons, outcomes, and study design (PICOS).

2

METHODS

Protocol and

registration

5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number.

N/A

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale.

3, 4

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify

additional studies) in the search and date last searched.

3, 4 ACCEPTED


35

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be

repeated.

3, 4

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis).

3, 4, Figure 1

Data collection

process

10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any

processes for obtaining and confirming data from investigators.

4

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and

simplifications made.

4

Risk of bias in

individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was

done at the study or outcome level), and how this information is to be used in any data synthesis.

4, 14, 15

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 4, 5

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis.

4, 5

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36

Table 5. PRISMA 2009 Checklist (cont.)

Section/topic # Checklist item Reported on

page #

Risk of bias across

studies

15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective

reporting within studies).

5

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done,

indicating which were pre-specified.

N/A

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for

exclusions at each stage, ideally with a flow diagram.

6, Figure 1

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up

period) and provide the citations.

6, Table 1

Risk of bias within

studies

19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 6, 7, Table 4

Results of individual

studies

20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each

intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

10, 11, Table 3,

Figure 2

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 10, 11, Figure 2

Risk of bias across

studies

22 Present results of any assessment of risk of bias across studies (see Item 15). 4, 5, 14, 15,

Figure 2

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item

16]).

N/A ACCEPTED


37

DISCUSSION

Summary of

evidence

24 Summarize the main findings including the strength of evidence for each main outcome; consider their

relevance to key groups (e.g., healthcare providers, users, and policy makers).

12, 13, 14

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval

of identified research, reporting bias).

14, 15

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future

research.

16

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders

for the systematic review.

N/A

ACCEPTED


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